Human herpesvirus 6 (HHV-6) is the common collective name for human herpesvirus 6A (HHV-6A) and human herpesvirus 6B (HHV-6B). These closely related viruses are two of the nine known herpesviruses that have humans as their primary host.
HHV-6A and HHV-6B are double-stranded DNA viruses within the Betaherpesvirinae subfamily and of the genus Roseolovirus. HHV-6A and HHV-6B infect almost all of the human populations that have been tested.
HHV-6A has been described as more neurovirulent, and as such is more frequently found in patients with neuroinflammatory diseases such as multiple sclerosis. HHV-6 (and HHV-7) levels in the brain are also elevated in people with Alzheimer's disease.
HHV-6B primary infection is the cause of the common childhood illness exanthema subitum (also known as roseola infantum or sixth disease). It is passed on from child to child. It is uncommon for adults to contract this disease as most people have had it by kindergarten, and once contracted, immunity arises and prevents future reinfection. Additionally, HHV-6B reactivation is common in transplant recipients, which can cause several clinical manifestations such as encephalitis, bone marrow suppression, and pneumonitis.
A variety of tests are used in the detection of HHV-6, some of which do not differentiate the two species.
Both viruses can cause transplacental infection and be passed on to a newborn.
HHV-6A and Infertility A 2016 study showed that 43% of women with unexplained infertility tested positive for HHV-6A compared to 0% in the fertile control group. HHV-6A was found present in endometrial epithelial cells from women with unexplained infertility but not in their blood. In the context of infertility, this discovery underscores the importance of targeted testing for HHV-6A within the uterine environment, as the virus was not detected in the bloodstream of the affected individuals. Effective diagnosis, therefore, requires tests that are capable of distinguishing between active and latent HHV-6A infections specifically in endometrial tissue, highlighting the need for tissue-specific viral detection methods in assessing and managing infertility associated with HHV-6A.
A 2018 study found 37% of women experiencing recurrent implantation failure after IVF/ET had HHV-6A in their endometrial biopsies, compared to 0% in control groups.
A 2019 study confirmed the presence of HHV-6A infection in 40% of idiopathic infertile women. Identifying the effect of HHV-6A infection on endometrial immune status opens up a new perspectives on fertility care. It is possible to choose antiviral therapies and non-hormonal approaches for women with unexplained infertility characterized by HHV-6A to increase their pregnancy rate.
Testing for HHV-6 The table below presents a comprehensive overview of various diagnostic tests used to detect human herpesvirus 6 (HHV-6), detailing their ability to distinguish between active and latent infections. It also includes insights on the interpretation of test results, identifies providers that offer these tests, and indicates which methods are suitable for detecting HHV-6A in the endometrial lining—an important consideration for evaluating potential causes of infertility in women. The table serves as a guide for healthcare professionals to select appropriate diagnostic tests for HHV-6. +Diagnostic Tests for HHV-6 Infection and Their Utility in Uterine Environment AnalysisExaminationActive vs. Latent Infection DetectionInsightsProvidersUterine Detection for InfertilityCovee™ (menstruating women only)Yes, it checks endometrial cells which are shed monthly.Only at-home sample collection option.Uses small amount (1-2ml) of menstrual fluid.Fertility PhoenixYesIgG Assessment via ELISANo, it only indicates prior exposure to the virus.A high ELISA score (>5) could suggest an active infection; however, only IFA-based tests can precisely quantify the antibody levels.Various laboratories offer ELISA testing. NoIgG Analysis by IFAYes, significantly raised levels compared to healthy norms suggest recent or ongoing infection.A low total IgG due to immune deficiency won't show increased titer levels. A singular rise in HHV-6 antibody levels may hint at an infection.Quest Diagnostics and ARUP Laboratories are known to provide IFA testing with specific median titer ranges.NoIgM ScreeningYes, present only during or shortly after active infection.Lack of IgM doesn't exclude the possibility of active infection, as chronic infections may not show IgM presence.IgM tests are widely available.NoPCR for HHV-6 in FluidsYes, presence in fluids suggests an acute infection.Negative results for HHV-6 DNA don't exclude tissue-based persistent infections. Repeat testing and whole blood analysis are recommended for thorough evaluation.PCR testing is a common service offered by many laboratories.NoWhole Blood PCR (Viral Load Count)Yes, viral load above a certain threshold indicates active infection.In healthy individuals, viral loads are usually below the detection limit of standard labs.PCR viral load testing is standard in many diagnostic labs.NoWhole Blood PCR (Presence/Absence)No, cannot distinguish between active and latent states.The majority of healthy individuals will have latent HHV-6B. This test helps identify the type of HHV-6 but not its activity.Not specified in the original table.NoImmunohistochemical TestingYes, can detect virus replication through protein expression.Can discern between HHV-6A and HHV-6B activity in fixed tissue.Coppe Laboratories YesTissue PCR (Qualitative)No, does not indicate if the virus is currently active.Tissue typing is possible; specimens should be promptly frozen for transport.ViracorIBT is mentioned as offering qualitative PCR testing on tissue samples.NoTissue PCR (Quantitative)Yes, discriminates between dormant low-level presence and active high-level infections.Requires a specific amount of tissue for analysis and different labs may have varying material requirements.Coppe Laboratories and Eurofins-Viracor are noted as providers, with Eurofins requiring 5 mg and Coppe 1 mg of material.YesddPCR for ciHHV-6 StatusNo, designed to confirm ciHHV-6 presence, not active infection.Recommended when ciHHV-6 infection is suspected by healthcare providers.This test was introduced by the University of Washington for identifying ciHHV-6.NociHHV-6 Status Testing using PCR of Hair follicle or finger nailNo, designed to confirm ciHHV-6 presence, not active infection.The Gold standard for determining ciHHV6Coppe LaboratoriesNo
History
During 1986, Syed Zaki Salahuddin, Dharam Ablashi, and Robert Gallo cultivated peripheral blood mononuclear cells from patients with AIDS and lymphoproliferative illnesses. Short-lived, large, refractile cells that frequently contained intranuclear and/or intracytoplasmic inclusion bodies were documented. Electron microscopy revealed a novel virus that they named human B-lymphotropic virus (HBLV).
Shortly after its discovery, Ablashi et al. described five cell lines that can be infected by the newly discovered HBLV. They published that HSB-2, a particular T-cell line, is highly susceptible to infection. Ablashi's pioneering research concluded by suggesting that the virus name be changed from HBLV to HHV-6, in accord with the published provisional classification of herpes viruses.
Years later, HHV-6 was divided into subtypes. Early research (1992) described two very similar, yet unique variants: HHV-6A and HHV-6B. The distinction was warranted due to unique restriction endonuclease cleavages, monoclonal antibody reactions, and growth patterns.
HHV-6A includes several adult-derived strains and its disease spectrum is not well defined, although it is thought by some to be more neurovirulent. HHV-6B is commonly detected in children with roseola infantum, as it is the etiologic agent for this condition. Within these two viruses is a sequence homology of 95%.
In 2012, HHV-6A and HHV-6B were officially recognized as distinct species.
Taxonomy HHV-6A and HHV-6B were recognized by the International Committee on Taxonomy of Viruses (ICTV) as distinct species in 2012. Human roseoloviruses include HHV-6A, HHV-6B and HHV-7.
Herpesvirus was established as a genus in 1971 in the first report of the ICTV. This genus consisted of 23 viruses among 4 groups. In 1976, a second ICTV report was released in which this genus was elevated to the family level — the herpetoviridae. Because of possible confusion with viruses derived from reptiles, the family name was changed in the third report (1979) to herpesviridae. In this report, the family Herpesviridae was divided into 3 subfamilies (alphaherpesvirinae, betaherpesvirinae and gammaherpesvirinae) and 5 unnamed genera; 21 viruses were recognized as members of the family.
In 2009, the order Herpesvirales was created. This was necessitated by the discovery that the herpes viruses of fish and molluscs are only distantly related to those of birds and mammals. Order Herpesvirales contains three families, the Herpesviridae, which contains the long-recognized herpesviruses of mammals, birds, and reptiles, plus two new families — the family Alloherpesviridae which incorporates herpes viruses of bony fish and frogs, and the family Malacoherpesviridae which contains viruses of molluscs.Davison AJ (2010) Herpesvirus systematics. Vet. Microbiol. 143(1–2): 52–69
As of 2012, this order currently has 3 families, 4 subfamilies (1 unassigned), 18 genera (4 unassigned) and 97 species.
Structure The diameter of an HHV-6 virion is about 2000 angstroms. The virion's outer portion consists of a lipid bilayer membrane that contains viral glycoproteins and is derived from that of the host. Below this membrane envelope is a tegument which surrounds an icosahedral capsid, composed of 162 capsomeres. The protective capsid of HHV-6 contains double stranded linear DNA.
During maturation of HHV-6 virions, human cell membranes are used to form viral lipid envelopes (as is characteristic of all enveloped viruses). During this process HHV-6 utilizes lipid rafts, which are membranous microdomains enriched by cholesterol, sphingolipids, and glycosylphosphatidylinositol-anchored proteins. Early researchers suspected that HHV-6 virions mature in the nucleus; some even incorrectly published this, as they generalized and applied to HHV-6 what was known about other viruses. However, researched published in 2009 suggests that the HHV-6 virus utilizes trans-Golgi-network-derived vesicles for assembly.
Genome The genetic material of HHV-6 is composed of linear (circular during an active infection), double stranded DNA which contains an origin of replication, two 8–10 kb left and right direct repeat termini, and a unique segment that is 143–145kb.
The origin of replication (often labeled as "oriLyt" in the literature) is where DNA replication begins. The direct repeat termini (DRL and DRR) possess a repeated TTAGGG sequence, identical to that of human telomeres. Variability in the number of telomeric repeats is observed in the range of 15–180. These termini also contain pac-1 and pac-2 cleavage and packing signals that are conserved among herpesviruses.
The unique segment contains seven major core gene blocks (U27–U37, U38–U40, U41–U46, U48–U53, U56–U57, U66EX2–U77, and U81–U82), which is also characteristic of herpesviruses. These conserved genes code for proteins that are involved in replication, cleavage, and packing of the viral genome into a mature virion. Additionally, they code for a number of immunomodulatory proteins. The unique segment also possesses a block of genes (U2–U19) that are conserved among HHV-6, HHV-7, and cytomegaloviruses (the betaherpesviruses). A number of the unique segment genes are associated with, for instance, the HCMV US22 family (). The table below outlines some of their known properties.
Genes